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Renal phenotypic variability in Townes-Brocks syndrome. Case report of family with biopsy proven focal segmental glomerulosclerosis.

Abstract 200 words
Main 1400 words


Townes-Brocks syndrome (TBS) is a rare autosomal dominant disease. It has a prevalence of 1 in 250,000 (1). Clinical phenotype is variable, however the core triad of malformations in TBS are anorectal malformations, hand malformations and external ear malformations associated with deafness(1). Over 60 mutations have been found in the SALL1 gene(2). SALL1 is an essential organogenesis regulator in urological, renal, limb, ear, brain and liver development (1).
Renal impairment is common in TBS patients. The incidence of renal malformations is between 20 - 62.5%. There is a large variety of clinical renal phenotype. Possible renal malformations include renal hypoplasia, renal dysplasia, renal agenesis, multicystic kidneys, vesicoureteric reflux, posterior urethral valve or meatal stenosis (1). It is a cause of early onset renal failure between the ages of 1 to 23 years, so early identification is vital (1).
We present a family with TBS and variable clinical phenotypes. Patients in our family presented to the renal services with renal impairment or proteinuria. Two of these family members underwent a renal biopsy that showed focal segmental glomerulosclerosis (FSGS). Previous renal histology in TBS has been limited to autopsy reports. These have found focal disorganization of renal cortex, cystic renal tubules and dysplastic areas(3). This contrasts with our patients who presented slightly older and with distinctively different histological features. It is unclear if the FSGS was a secondary phenomenon due to the renal dysplasia but the patients that had a renal biopsy had normal sized kidneys on ultrasound and hence underwent the biopsy.

Case report

The family pedigree is shown in Figure 1. The index case was IS.

Patient 1 - IS

IS presented to the renal services with proteinuria in 1990, 8 years after the birth of her third child aged 37. Since 1982, post partum, she was obese. With the history of obesity for 8 years and family history of FSGS a renal biopsy was not undertaken. Renal function at this time was … IS was diagnosed with hypothyroidism when the proteinuria was identified, she suffered with premature depigmentation of her hair aged 30. Bariatric surgery was undertaken in 2009 due to Type 2 diabetes mellitus. Despite the history of TBS in her husband’s pedigree she was not related to him, and they were from different regions in Ireland. She did not have any of the typical phenotypic features of TBS (imperforate anus, dysplastic ears and thumb malformations)

Patient 2 - SS

SS was born with bilateral cauliflower ears and severe sensorineural deafness. He did not have the typical thumb malformations however, was born with talipes equinovarus. Nor did he have an imperforate anus but had Hirschsprung’s disease and required surgery with a colostomy formation. SS also suffers with schizophrenia. He has mild renal impairment with a serum creatinine of 116 micromol/L in 2004, but has since been lost to follow up.

Patient 3 - LS

LS presented in 2008 with proteinuria and abnormal renal function (?? What) at the age of 30. A biopsy was undertaken, which revealed a late, severe focal segmental sclerosing glomerular disorder. LS’s past medical history included an imperforate anus that had been corrected as a neonate, dysplastic ears but no thumb malformations. He also had a history of hypertension, osteoarthritis and  migraine. Chronic kidney disease progressed necessitating renal replacement therapy and LS had a pre-emptive renal transplant in October 2011. Proteinuria continued following transplantation, and increased further on conversion of mycophenolate mofetil (MMF) to sirolimus; switch undertaken due to CMV colitis and persistent CMV viraemia. A renal allograft biopsy was undertaken at this point which showed acute cellular rejection, treated successfully with methylprednisolone. Acne was induced by sirolimus, the tetracycline used to treat acne caused cerebral hypertension and so he was converted back to MMF. LS developed new onset diabetes after transplantation in 2015. He also has some mood disorders and suffers from severe anxiety and does not like to talk about his medical condition.

Patient 4 - TS

Presented at the age of 16 during her first pregnancy with proteinuria. Aged 19 in view of the continued renal impairment and proteinuria a renal biopsy was undertaken in 1995. The renal biopsy demonstrated focal segmental sclerosing glomerular lesions, similar to LS but with less chronic damage and at an earlier stage with fewer glomerular lesions. TS also suffered with obesity. Renal function progressively declined, necessitating a pre-emptive renal transplant in 2008. She had a 16 year old deceased donor with a mismatch grade of 0-0-0. Despite this she had borderline cellular rejection at a 3 month protocol renal biopsy. Complications post transplantation included cervical intra-epithelial neoplasia grade 3 and diarrhoea induced by MMF. TS has 4 children, but there is no history of TBS in them (?true). She did not have the typical TBS triad features but has the SALL1 mutation (??). There is a history of hypertension since 2003 and she has recently suffered with depression and anxiety.

Patient 5 - BS

BS presented with reduced glomerular filtration rate; he had mild renal hypoplasia and a small left kidney. The tyoical TBS triad was not present however he had bilateral sensorineural hearing loss since the age of 8 and episodes of recurrent central abdominal pain with diarrhoea on ingestion of potatoes. Additionally he was hypertensive since 2011 and like his siblings suffered with mood difficulties. BS had severe anxiety since 2012 (aged 20) with auditory hallucinations and as a result is housebound.

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